The present invention is generally in the area of immunoregulation, and is particularly the selective hormone-mediated modulation of lymphocyte production in bone marrow.
The production of lymphocytes and other blood cells is a carefully regulated process that is essential for maintenance of a normal immune system. B lymphocytes, which upon activation differentiate into plasma cells that secret antibodies, originate in bone marrow from stem cell precursors. Another major category of lymphocytes, T lymphocytes, is made in the thymus from stem cell precursors. Together these lymphocytes are responsible for both the humoral (antibody) mediated immune response and the cell mediated immune response.
Studies of molecular regulators of B lymphopoiesis have focused on aspects that might be organ, i.e., bone marrow, specific, though no regulatory molecules have been found that are unique in distribution to that tissue. Blood cell formation within bone marrow is thought to be controlled in part by close cellular interactions and the availability of cytokines that induce proliferation and differentiation of committed precursor cells. However, understanding of the proliferative, developmental, and differentiative aspects of this process is incomplete, especially of mechanisms that inhibit or increase the production of particular blood cell types.
There is a gradual involution of the thymus with age, but the mechanism through which this occurs is only partially understood. It has long been known that the thymus involutes further during pregnancy and regrows after delivery. This phenomenon is believed to be regulated in part by hormones, because estrogen injections have been observed to cause thymus atrophy similar to that associated with pregnancy. However, the immune system is thought to function normally during pregnancy; that is, the host defense against pathogens appears to be intact.
A better understanding of the influence of hormones on the humoral immune system is needed. This information may be relevant to maternal-fetal relationships during pregnancy and abnormalities involving them, and to the pathophysiologic mechanisms of autoimmune diseases such as systemic lupus erythematosus (SLE), which are commonly diagnosed or may worsen during pregnancy. Information on the effects of hormones on the humoral immune system may also be relevant in cyclic neutropenia and diseases in which antibodies are directed against cell components. An increased awareness of the effects of hormone administration may also be helpful in treating immune deficiency diseases, especially those in which the numbers of lymphocytes are abnormal, and in preventing iatrogenic disease or the side effects of hormone replacement therapy, as in the use of hormones in the treatment of osteoporosis. It may also be possible to use this basic information to manipulate immunologic tolerance and achieve immunosuppression, or alternatively, with agents that interfere with the synthesis or activity of hormones, to augment the humoral immune system. Moreover, methods for propagating lympho-hemopoietic progenitor cells and stem cells in culture might be improved by manipulation of hormone concentrations in cell culture medium.
It is therefore an object of the present invention to provide a method for immunomodulation through manipulation of specific classes of immune cells, especially B lymphocytes, by administration of compounds having an effect on the number of B lymphocyte precursors and on the resulting number of newly formed B lymphocytes and plasma cells.
It is a further object of the present invention to provide methods and means for manipulation of B lymphocytes and their precursor cells and plasma cells involved in autoimmune disorders, osteoporosis, and cyclic neutropenia.
It is another object of the present invention to provide methods and means for manipulation of B lymphocytes and their precursor cells and plasma cells involved in immune deficiency diseases.
It is yet another object of the present invention to provide methods and means to improve cell culture of the cells of bone marrow and its stroma.